Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

Jonathan P Gumucio, Austin H Qasawa, Patrick J Ferrara, Afshan N Malik, Katsuhiko Funai, Brian McDonagh, Christopher L Mendias

Posted on: 7 January 2019

Preprint posted on 18 November 2018

Article now published in The FASEB Journal at

Why do lipids accumulate following muscle injury? A multi-omics study points to mitochondrial and lipid metabolism dysfunction.

Selected by Pablo Ranea Robles


Do you know anyone that had a muscle injury while heavy lifting or practicing sports? Sure you do. Chronic muscle injuries provoke the loss of mobility in the patients, imposing a burden on health care and workers’ compensation systems. Among the muscles usually prone to injury, the rotator cuff is one of the most affected. The rotator cuff is a group of muscles and tendons that stabilize the shoulder joint and let us lift and rotate our arms (Figure 1).

Rotator cuff anatomy

Figure 1. The anatomy of the human rotator cuff. Credit: Harvard Health Publishing


Have you ever wondered what changes happen in that injured muscle after the injury? One of the best characterized effects of muscle injury is pathological lipid accumulation. This is known as myosteatosis (from the Greek words myos-, muscle, steatos-, fat, and -osis, formation). The rotator cuff is particularly susceptible to develop pathological lipid accumulation after injury.  Importantly, lipid accumulation in this muscle after injury correlates with a poor outcome after surgical repair (Gladstone et al., 2007). Moreover, recurrence of tears after the injury is quite common in this type of injuries (Isaac et al., 2012). It is known that lipid excess likely impairs muscle regeneration, but the mechanisms driving lipid accumulation in myosteatosis remain largely unknown.

In this study, Gumucio and coworkers used a rat model of rotator cuff injury (Gumucio et al., 2018). The anatomy of the rotator cuff in rats is similar to humans, and this model mimics many of the pathological changes observed in patients with chronic rotator cuff tears (Soslowsky et al., 1996). They studied the supraspinatus muscle, one of the muscles of the rotator cuff (supraspinatus, infraspinatus, teres minor, and subscapularis). Experimental groups were uninjured and injured rats, either 10, 30, or 60 days after the injury. They aimed to characterize the biochemical and cellular pathways that lead to myosteatosis after skeletal muscle injury.

Key findings

They characterized the changes in muscle fiber force production and the biological changes after injury by the integration of different -omics techniques. They evaluated alterations in the rotator cuff transcriptome (by RNA sequencing), proteome, metabolome, and lipidome (using mass spectrometry). The main outcome was the identification of mitochondrial dysfunction and impaired fatty acid oxidation as strong drivers of the pathological steatosis after muscle injury. Then, they studied in detail the hypothesis that mitochondrial dysfunction drives pathological lipid accumulation in torn rotator cuff muscles.

Shotgun lipidomics revealed expected increases in different lipid species at different time points in the injured muscles, such as free fatty acids (FFA), triglycerides, ceramides, sphingomyelins, and some phospholipids. Other lipids displayed a biphasic response, like cholesterol esters, diacylglycerides, and other phospholipids.

The metabolomics data revealed a decrease in nucleoside and nucleotide metabolites, concomitant with an increase in glycolytic and pentose phosphate pathway metabolites. The transcriptomics data showed an induction of well-known pathways in muscle injury, such as autophagy, atrophy, inflammation or fibrosis. It is worth to highlight the decreased mRNA expression of genes involved in mitochondrial function (Krebs cycle and OXPHOS system), lipid uptake and metabolism, and fatty acid oxidation, which was confirmed by proteomics data. Another aspect that appeared in the transcriptomics and proteomics data is oxidative stress. This is deduced due to the increase reactive oxygen species (ROS)-related genes and proteins amount. Moreover, omega-oxidation and peroxisomal metabolism were induced, since transcriptomics data showed augmented expression of Acox1 (Acyl-CoA oxidase 1, an enzyme of peroxisomal beta-oxidation) and Cyp4b1 (from the cytochrome P450 family, related to omega-oxidation of fatty acids). These pathways are usually active when mitochondrial fatty acid oxidation is impaired. These data, together with the increased glycolytic metabolites point to a metabolic shift in injured muscles, from fatty acid oxidation and oxidative phosphorylation to glycolysis.

Finally, a deeper study on mitochondrial function demonstrated that mitochondrial metabolism is impaired in injured muscles, as shown by a reduction in the activity of complexes I, II, and IV, an increase of some antioxidant proteins, and a reduction in the oxidation rate of pyruvate and palmitate. However, mitochondrial content seems to be equal in injured and non-injured muscles, since mitochondrial DNA levels were similar in both groups.

Future directions and questions for authors

Some aspects of this study deserve more attention. For instance, what is the shape of mitochondria in injured muscles? Are they smaller or bigger? Is there peroxisomal proliferation in injured muscles, given the increase of peroxisomal metabolism? Which are the species of acylcarnitines measured? If fatty acid oxidation is impaired, one would expect an increase in some of the acylcarnitines species. Is there autophagy impairment in the injured muscles? The p62 accumulation observed in injured muscles is a classical marker of autophagy impairment. After this study, it would be of interest to know which the next steps are. Can these altered pathways be modulated by drugs? In this way, we would be able to study their effect on muscle regeneration after injury. It would be also of interest to compare human samples from injured muscles with non-injured muscles, to see if these changes are conserved. Finally, one important weakness of this study is that it has been performed only in male rats. Fat content and metabolism is different between men and women, so more studies in female individuals of animal models need to be done to fully understand the pathophysiology of muscle injuries.

What I liked about the study

I liked that the authors integrated different -omics data to gain insights into the molecular physiology of muscle injury. This kind of unbiased approach can shed light on hidden pathological mechanisms. Here, they uncovered a central role of mitochondrial and lipid metabolism in the development of myosteatosis after muscle injury.



Gladstone, J. N., Bishop, J. Y., Lo, I. K. Y. and Flatow, E. L. (2007). Fatty Infiltration and Atrophy of the Rotator Cuff do not Improve after Rotator Cuff Repair and Correlate with Poor Functional Outcome. Am. J. Sports Med. 35, 719–728.

Gumucio, J. P., Qasawa, A. H., Ferrara, P. J., Malik, A. N., Funai, K., McDonagh, B. and Mendias, C. L. (2018). Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis. bioRxiv 471979.

Isaac, C., Gharaibeh, B., Witt, M., Wright, V. J. and Huard, J. (2012). Biologic approaches to enhance rotator cuff healing after injury. J. shoulder Elb. Surg. 21, 181–90.

Soslowsky, L. J., Carpenter, J. E., DeBano, C. M., Banerji, I. and Moalli, M. R. (1996). Development and use of an animal model for investigations on rotator cuff disease. J. shoulder Elb. Surg. 5, 383–92.

Tags: lesion, muscular, rehabilitation


Read preprint (No Ratings Yet)

Have your say

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

Also in the biochemistry category:

Notch3 is a genetic modifier of NODAL signalling for patterning asymmetry during mouse heart looping

Tobias Holm Bønnelykke, Marie-Amandine Chabry, Emeline Perthame, et al.

Selected by 06 June 2024

Bhaval Parmar

Developmental Biology

14-3-3 binding regulates Tau assembly and microtubule association

Janine Hochmair, Maxime C. M. van den Oetelaar, Lisa Diez, et al.

Selected by 03 May 2024

Barbora Knotkova et al.


Structural basis of respiratory complexes adaptation to cold temperatures

Young-Cheul Shin, Pedro Latorre-Muro, Amina Djurabekova, et al.

Selected by 10 April 2024

Pamela Ornelas


Also in the pathology category:

LINC complex alterations are a hallmark of sporadic and familial ALS/FTD

Riccardo Sirtori, Michelle Gregoire, Emily Potts, et al.

Selected by 03 June 2024

Megane Rayer et al.

Cell Biology

Hypoxia blunts angiogenic signaling and upregulates the antioxidant system in elephant seal endothelial cells

Kaitlin N Allen, Julia María Torres-Velarde, Juan Manuel Vazquez, et al.

Selected by 13 September 2023

Sarah Young-Veenstra


H2O2 sulfenylates CHE linking local infection to establishment of systemic acquired resistance

Lijun Cao, Heejin Yoo, Tianyuan Chen, et al.

Selected by 23 August 2023

Marc Somssich

Plant Biology

Also in the physiology category:

Blue appendages and temperature acclimation increase survival during acute heat stress in the upside-down jellyfish, Cassiopea xamachana

Megan E. Maloney, Katherine M. Buckley, Marie E. Strader

Selected by 30 April 2024

Maitri Manjunath

Animal Behavior and Cognition

How the liver contributes to stomach warming in the endothermic white shark Carcharodon carcharias

David C. Bernvi, Geremy Cliff

Selected by 22 April 2024

Sarah Young-Veenstra


Unlocking the secrets of kangaroo locomotor energetics: Postural adaptations underpin increased tendon stress in hopping kangaroos

Lauren H. Thornton, Taylor J.M. Dick, John R. Hutchinson, et al.

Selected by 25 March 2024

EMB EMB_Liv et al.


preLists in the biochemistry category:

BSCB-Biochemical Society 2024 Cell Migration meeting

This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.


List by Reinier Prosee

Preprint Peer Review – Biochemistry Course at UFRJ, Brazil

Communication of scientific knowledge has changed dramatically in recent decades and the public perception of scientific discoveries depends on the peer review process of articles published in scientific journals. Preprints are key vehicles for the dissemination of scientific discoveries, but they are still not properly recognized by the scientific community since peer review is very limited. On the other hand, peer review is very heterogeneous and a fundamental aspect to improve it is to train young scientists on how to think critically and how to evaluate scientific knowledge in a professional way. Thus, this course aims to: i) train students on how to perform peer review of scientific manuscripts in a professional manner; ii) develop students' critical thinking; iii) contribute to the appreciation of preprints as important vehicles for the dissemination of scientific knowledge without restrictions; iv) contribute to the development of students' curricula, as their opinions will be published and indexed on the preLights platform. The evaluations will be based on qualitative analyses of the oral presentations of preprints in the field of biochemistry deposited in the bioRxiv server, of the critical reports written by the students, as well as of the participation of the students during the preprints discussions.


List by Marcus Oliveira

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.


List by Nadja Hümpfer et al.

20th “Genetics Workshops in Hungary”, Szeged (25th, September)

In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link:


List by Nándor Lipták


The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!


List by Osvaldo Contreras

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)


List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019


List by Dey Lab

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.


List by Pablo Ranea Robles


This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.


List by Sandra Franco Iborra